The pattern recognition receptor, RAGE (Receptor for Advanced Glycation Endproducts) is a multiligand receptor that is a member of the immunoglobulin (Ig) superfamily. RAGE binds AGEs and other ligands, including high mobility group box 1 (HMGB1, also known as HMG-1, HMG1 and amphoterin), amyloid β-peptide, S100/calgranulin family proteins and leukocyte integrins (e.g., Mac-1) (Schmidt, A. et al., J. Clin. Invest. 108:949-955 (2001); Chavakis, T. et al., J. Exp. Med. 198:1507-1515 (2003)). RAGE is expressed at low levels in normal tissues and vasculature, but becomes upregulated when its ligands accumulate (Schmidt, A. et al., J. Clin. Invest. 108:949-955 (2001)). Binding of ligands to RAGE initiates a sustained period of cellular activation that is mediated by receptor-dependent signaling. In addition, the upregulation and enhanced surface expression of RAGE in environments rich in RAGE ligands allows the receptor to propagate cellular dysfunction in a number of pathophysiological conditions, such as diabetes, amyloidoses, immune and inflammatory disorders, and tumors (Schmidt, A. et al., id.).
An important ligand for RAGE is HMGB1, which has been implicated as a cytokine mediator of a number of inflammatory conditions. Inflammation is often induced by proinflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1α; IL-1β, IL-6, macrophage migration inhibitory factor (MIF), and other compounds. These proinflammatory cytokines are produced by several different cell types, including immune cells (for example, monocytes, macrophages and neutrophils), as well as non-immune cells, such as fibroblasts, osteoblasts, smooth muscle cells, epithelial cells, and neurons. These proinflammatory cytokines contribute to various disorders during the early stages of an inflammatory cytokine cascade.
The early proinflammatory cytokines (e.g., TNF, IL-1α, IL-1β, IL-6, MIF, etc.) mediate inflammation, and induce the late release of HMGB1, a protein that accumulates in serum and mediates delayed lethality and further induction of early proinflammatory cytokines. The HMGB1 molecule has three domains: two DNA binding motifs termed HMGB A and HMGB B boxes, and an acidic carboxyl terminus. The two HMGB boxes are highly conserved 80 amino acid, L-shaped domains.
Given the importance of RAGE and its ligands (e.g., HMGB1) in a number of significant human disorders (e.g., diabetes, cancer, chronic inflammatory diseases, diabetes, amyloidoses, cardiovascular diseases and other inflammatory diseases), it would be beneficial to identify agents that could be useful for treating disorders mediated by RAGE and its ligands.